Systems and methods for use in emission guided radiation therapy

ABSTRACT

Described herein are systems and methods for positioning a radiation source with respect to one or more regions of interest in a coordinate system. Such systems and methods may be used in emission guided radiation therapy (EGRT) for the localized delivery of radiation to one or more patient tumor regions. These systems comprise a gantry movable about a patient area, where a plurality of positron emission detectors, a radiation source are arranged movably on the gantry, and a controller. The controller is configured to identify a coincident positron annihilation emission path and to position the radiation source to apply a radiation beam along the identified emission path. The systems and methods described herein can be used alone or in conjunction with surgery, chemotherapy, and/or brachytherapy for the treatment of tumors.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Prov. Pat. Appl. No.61/470,432, filed on Mar. 31, 2011, which is hereby incorporated byreference in its entirety.

BACKGROUND

Radiation therapy involves delivering tumoricidal doses of radiation tolocalized regions of the body. Stereotactic radiation therapy, alsocalled radiosurgery, may be used to treat tumors in the brain, breast,head, neck, lung, liver, pancreas, spine, and prostate. Various tumorlocalization techniques may be used to precisely determine the locationof tumor(s) to help ensure that a high dose of radiation is delivered tothe tumor(s), while sparing healthy, non-cancerous tissue. For example,on-board imaging technologies such as single and stereoscopic x-rayimaging, kilovoltage and megavoltage CT imaging, implantable fiducialmarkers and transponders, ultrasound imaging, MRI, and others may helpto improve the efficacy of radiation therapy by gathering tumor locationinformation such that a radiation beam may be specifically targeted atthe tumor region. Various radiation beam-shaping techniques may also beused to help direct radiation precisely at the tumor(s) to be treated,while reducing the radiation exposure to surrounding tissue.

BRIEF SUMMARY

Described herein are systems and methods for positioning a radiationsource with respect to one or more regions of interest in a coordinatesystem. In some variations, such systems and methods may be used foremission guided radiation therapy (EGRT) for the localized delivery ofradiation to one or more patient tumor regions. EGRT systems maycomprise a gantry movable about a patient area, where one or morepositron emission detectors and radiation sources are arranged movablyon the gantry. The EGRT system may comprise a controller configured toidentify a coincident positron annihilation emission path and to directthe radiation source to apply a radiation beam along the identifiedemission path. Various methods may be used with an EGRT system toregulate the radiation beam that is applied to the target region(s) suchthat radiation is delivered to the target region(s) while reducing oravoiding the delivery of radiation to other tissue regions. The EGRTsystems and methods described herein may be used alone or in conjunctionwith surgery, chemotherapy, and/or brachytherapy for the treatment oftumors.

One example of an EGRT system described herein may comprise a gantrymovable about a patient area, one or more positron emission detectors,one or more therapeutic radiation sources, a motion system, and amicroprocessor. Some variations of EGRT systems may comprise one or moresingle-photon emission detectors. The therapeutic radiation sources maybe one or more radioactive materials, x-ray source(s), or particle beamsource(s). The positron emission detectors and the therapeutic radiationsources may be positioned at various locations around the gantry for thedetection of coincident positron annihilation emission paths thatintersect with a target region and the application of radiation beams todeliver a prescribed radiation dose to the target region. The radiationbeams may be applied along the emission paths and/or at a targetlocation determined based on the detected emissions. The movable gantrymay adjust the position of the positron emission detectors and/ortherapeutic radiation sources such that various regions of tissue may betreated within the patient area.

The methods described herein may be used with an EGRT system to regulatethe radiation beam that is applied to the target region(s) in order todeliver radiation to the target region(s) while reducing or avoiding thedelivery of radiation to other tissue regions. For example, EGRT methodsmay be used to deliver a prescribed dose of radiation to a target volumewhile avoiding the delivery of radiation to radiation-sensitivestructures, compensate for PET signal and/or radiation beam attenuation,collect real-time tumor location data, and perform other functions tohelp ensure that a tumoricidal level of radiation is delivered to thetarget volume while preserving surrounding tissue. The EGRT systems andmethods described herein may be used alone or in conjunction withsurgery, chemotherapy, radiosensitizers, and/or brachytherapy for thetreatment of tumors. For example, EGRT systems and methods may be usedbefore and/or after chemotherapy. EGRT may also be used before and/orafter surgery and/or brachytherapy. Some variations of tumor treatmentplans may comprise surgically removing a portion of the tumor, andtreating any remaining tumor masses with chemotherapy and/or EGRT. Thevarious therapies in a tumor treatment plan may be determined in part bythe size, type, location, progression and etiology of the tumor(s), aswell as a variety of patient variables (e.g., gender, age, allergies,tolerance to certain pharmacological agents, etc.).

One example of a method for emission guided radiation therapy for atarget region of tissue may comprise detecting a single coincidentpositron annihilation emission path that intersects both a target tissueand a radiation-sensitive tissue to be spared using a positron emissiondetector, and selectively applying radiation along the emission pathsuch that radiation applied to the target tissue is greater thanradiation applied to the tissue to be spared. In some variations,applying the radiation along the emission path may comprise emittingradiation in a probabilistic manner, or emitting radiation that has beenintensity-modulated in a probabilistic manner.

Another example of an EGRT method for applying radiation to a targetedregion of tissue may comprise detecting a single coincident positronannihilation emission path that intersects a target tissue region usinga positron emission detector, determining whether the emission pathintersects an organ structure, positioning a radiation source to applyradiation along the emission path, and applying radiation along theemission path, where the radiation has been modified by a probabilisticcoefficient. In some variations, applying radiation may compriseapplying radiation where the intensity of the radiation has been scaledby the probabilistic coefficient.

Another method for EGRT of a target region of tissue may comprisedetecting a single coincident positron annihilation emission path thatintersects a target region of tissue, where the emission path issubstantially perpendicular to a pre-determined margin of extension fromthe target tissue, and applying a radiation beam to the target tissuealong the emission path using a radiation source, where a width of theradiation beam may correspond to a width of the margin of extension. Insome variations, the target tissue is a PET-avid tissue and the marginof extension may comprise tissue adjacent to the PET-avid tissue.

Another method for EGRT of a target region of tissue may comprisedetecting boundaries of a PET-avid region of tissue using a positronemission detector, defining an extension region beyond the boundaries ofthe PET-avid region, detecting a single coincident positron annihilationemission path that intersects with a selected region of tissue, wherethe detected emission path may be substantially perpendicular to an axisof the extension region, and applying a radiation beam along thedetected emission path that may have a width that corresponds to a widthof the extension region. In some variations, the positron emissiondetector may be configured to determine the boundaries of the PET-avidregion of tissue region based on the detected positron annihilationemission paths.

Another method for EGRT of a target region of tissue may comprisedetecting boundaries of a PET-avid region of tissue using a positronemission detector that is configured to determine the boundaries of thePET-avid region of tissue, defining an extension region beyond theboundaries of the PET-avid region, detecting a single coincidentpositron annihilation emission path that intersects with a selectedregion of tissue, where the detected emission path may be substantiallyperpendicular to an axis of the extension region, and applying aradiation beam along the detected emission path that has a width thatmay correspond to a width of the extension region. In some variations,defining an extension region may comprise using an image obtained by oneor more of computed tomography, magnetic resonance imaging, PET, or anyother suitable imaging modality.

Another example of a method for EGRT of a target region of tissue maycomprise detecting a single coincident positron annihilation emissionpath using a positron emission detector, where the emission path mayintersect a first PET-avid region of tissue to be spared and a secondPET-avid region of tissue to be treated, positioning a radiation sourceat a location from which the radiation source may be capable of applyingradiation along the emission path, and applying radiation along theemission path, where the radiation may be adjusted according to amodulation factor that is inversely proportional to a projection of thefirst PET-avid region of tissue on the location of the radiation source.In some variations, applying radiation may comprise applying radiationbeams with a time duration that is modified by the modulation factor.Alternatively or additionally, applying radiation may comprise applyingradiation with an intensity that is modified by the modulation factor.In other variations, the second PET-avid region of tissue may intersectwith a target region of tissue, and the first region of tissue may notintersect with the target region of tissue.

Yet another method for EGRT of a target region of tissue may comprisedetecting a single coincident positron annihilation emission path usinga positron emission detector, where the emission path intersects atargeted region of tissue, and applying radiation along the emissionpath using a radiation source, where the radiation applied may beadjusted according to the total attenuation of the detected positronannihilation emission along the complete emission path as may bedetermined by an alternate imaging modality. In some variations, theapplied radiation may be adjusted according to the attenuation of thetherapeutic radiation along the positron annihilation emission path. Forexample, the applied radiation may be directly proportional or inverselyproportional to the attenuation of the detected positron annihilationemission. Examples of alternate imaging modalities may include computedtomography, magnetic resonance imaging, x-ray, and/or any suitableimaging modality.

Another example of a method for EGRT may comprise detecting a singlepositron annihilation emission path using a positron emission detector,where the emission path intersects a target region of tissue, computingan attenuation factor of the emission path using an image of the targetregion of tissue acquired by a selected imaging modality, and applyingradiation along the emission path, where the radiation is modulated bythe attenuation factor. In some variations, the radiation may beadjusted to compensate for the attenuation of the radiation along thepositron annihilation emission path. The applied radiation may beproportional or inversely proportional to the attenuation of thedetected positron annihilation emission. In some variations, theselected imaging modality may be computed tomography. In somevariations, the intensity of the radiation may be modulatedproportionally or inversely proportionally to the attenuation factor.Additionally or alternatively, the applied radiation may have a timeduration that may be modulated proportionally or inverselyproportionally to the attenuation factor. For example, the radiationapplied along the emission path may have a frequency that may bemodulated inversely proportionally to the attenuation factor.

One variation of a system for EGRT may comprise a gantry movable about apatient area, where the gantry comprises a rotatable inner gantry and arotatable outer gantry, a plurality of positron emission detectorsarranged movably along the inner gantry configured to detect a pluralityof positron annihilation emission paths within the patient area, and aradiation source arranged movably along on the outer gantry, wherein theradiation source is configured to apply radiation along each of theplurality of positron annihilation emission paths within the patientarea. In some EGRT systems, the inner gantry may be capable of rotatingat a higher rate than the outer gantry. In some variations, the systemmay comprise a sense mode where the plurality of positron emissiondetectors obstructs the radiation source, and a firing mode where theradiation source is unobstructed and is able to apply radiation to thepatient area. Alternatively or additionally, the EGRT system maycomprise one or more single photon emission detectors arranged movablyalong the inner gantry. In some variations, the radiation source mayalso comprise a collimator.

An example of a method for emission guided radiation therapy maycomprise detecting a positron annihilation emission path that intersectswith a plurality of target tissue regions using a plurality of positronemission detectors, positioning a radiation source to apply radiationalong each of the plurality of emission paths, and applying radiationalong each of the emission paths to deliver radiation to the pluralityof target tissue regions.

Another example of a system for EGRT may comprise a gantry movable abouta patient area, where the gantry comprises a rotatable inner gantry anda rotatable outer gantry, a plurality of positron emission detectorsarranged movably along the inner gantry configured to detect a pluralityof positron annihilation emission paths from a plurality of movingPET-avid regions within the patient area, and a radiation sourcearranged movably along on the outer gantry, where the radiation sourcemay be configured to apply radiation to each of the plurality ofPET-avid regions within the patient area. In some EGRT systems, theinner gantry may be capable of rotating at a higher rate than the outergantry. In some variations, the EGRT system may comprise a sense modewhere the plurality of positron emission detectors obstructs theradiation source, and a firing mode where the radiation source isunobstructed and is able to apply radiation to the patient area.Alternatively or additionally, the EGRT system may comprise one or moresingle photon emission detectors arranged movably along the innergantry. In some variations, the radiation source may also comprise acollimator.

An example of a method for EGRT may comprise detecting a positronannihilation emission path that intersects with a plurality of movingtarget tissue regions using a plurality of positron emission detectors,positioning a radiation source to apply radiation along the emissionpath, and applying radiation to the plurality of moving target tissueregions along a path derived from shifting the detected emission pathaccording to the movement of the target tissue regions.

Also described herein are systems that may be used for positioning aradiation source (such as a radiation source that may be used in asystem for EGRT). One variation of a system for positioning a radiationsource may comprise a circular gantry, a radiation source mounted on thegantry, positron emission detectors mounted on the gantry, and acontroller in communication with the radiation source and the positronemission detectors. The positron emission detectors may be configured todetect a positron emission path originating from a first region ofinterest within a coordinate system and the controller may be configured(e.g., by programming an algorithm that is stored in memory) to positionthe radiation source along the emission path. The radiation source maybe configured (e.g., by a program stored in memory and/or one or moresignals from the controller) to generate radiation according to aselected probabilistic coefficient. In some variations, the controllermay be configured to determine whether the emission path intersects asecond region of interest within the coordinate system, and theradiation source may be configured to generate radiation along theemission path according to the selected probabilistic coefficient if theemission path intersects the second region of interest. Alternatively oradditionally, the radiation source may be configured to generateradiation along the emission path if the emission path intersects thesecond region of interest and the selected probabilistic coefficient isbelow a pre-programmed probability threshold. In some variations, theradiation source may be configured to generate radiation that has beenintensity-modulated in a probabilistic manner along the emission path,and/or may be configured to generate radiation that has been scaled bythe probabilistic coefficient.

Another variation of a system for positioning a radiation source maycomprise a circular gantry, a radiation source mounted on the gantry,positron emission detectors mounted on the gantry, and a controller incommunication with the radiation source and the positron emissiondetectors. The positron emission detectors may be configured to detectmultiple positron emission paths originating from a plurality of regionsof interest within a coordinate system and the controller may beconfigured (e.g., by programming an algorithm that is stored in memory)to position the radiation source along the multiple emission paths.

Another variation of a system for positioning a radiation source maycomprise a circular gantry, a radiation source mounted on the gantry,positron emission detectors mounted on the gantry, and a controller incommunication with the radiation source and the positron emissiondetectors. The positron emission detectors may be configured to detect apositron emission path that intersects a plurality of moving regions ofinterest within a coordinate system and the controller may be configured(e.g., by programming an algorithm that is stored in memory) to positionthe radiation source along a path derived by shifting the detectedemission path according to the movement of the regions of interest.

One variation of a system for positioning a radiation source maycomprise a circular gantry, a radiation source mounted on the gantry,positron emission detectors mounted on the gantry, and a controller incommunication with the radiation source and the positron emissiondetectors. The positron emission detectors may be configured detect to apositron emission path that intersects a region of interest within acoordinate system, where the emission path may be substantiallyperpendicular to a pre-determined direction of margin of extension fromthe region of interest. The controller may be configured (e.g., byprogramming an algorithm that is stored in memory) to position theradiation source along the emission path, and the radiation source maybe configured (e.g., by a program stored in memory and/or one or moresignals from the controller) to generate a radiation beam with a widththat corresponds to a width of the margin of extension. In somevariations, the region of interest may be PET-avid and the margin ofextension may comprise a region adjacent to the PET-avid region ofinterest.

One variation of a system for positioning a radiation source maycomprise a circular gantry, a radiation source mounted on the gantry,positron emission detectors mounted on the gantry, and a controller incommunication with the radiation source and the positron emissiondetectors. The positron emission detectors may be configured to detectboundaries of a PET-avid region of interest within a coordinate systemand to detect a single coincident positron annihilation emission paththat intersects with a second region of interest within the coordinatesystem. The controller may be configured (e.g., by programming analgorithm that is stored in memory) to define an extension region beyondthe boundaries of the PET-avid region of interest and to determinewhether the detected emission path is substantially perpendicular to anaxis of the extension region, and to position the radiation source alongthe emission path. The radiation source may be configured (e.g., by aprogram stored in memory and/or one or more signals from the controller)to generate a radiation beam with a width that corresponds to a width ofthe extension region. In some examples, the controller may be configuredto define an extension region by using an image obtained by computedtomography and/or magnetic resonance imaging.

Another variation of a system for positioning a radiation source maycomprise a circular gantry, a radiation source mounted on the gantry,positron emission detectors mounted on the gantry, and a controller incommunication with the radiation source and the positron emissiondetectors. The positron emission detectors may be configured to detect asingle positron annihilation emission path that intersects a region ofinterest within a coordinate system. The controller may be configured(e.g., by programming an algorithm that is stored in memory) to computean attenuation factor of the emission path using an image of the regionof interest acquired by a selected imaging modality, and to position theradiation source along the emission path. The radiation source may beconfigured (e.g., by a program stored in memory and/or one or moresignals from the controller) to generate radiation that is modulated bythe attenuation factor. The selected imaging modality may be computedtomography and/or magnetic resonance imaging. In some examples, theradiation source may be configured to generate radiation that isadjusted to compensate for attenuation of the radiation along thepositron annihilation emission path. Alternatively or additionally, theradiation source may be configured to generate radiation that isproportional to the attenuation of the detected positron annihilationemission path. In other examples, the radiation source may be configuredto generate radiation that is inversely proportional to the attenuationof the detected positron annihilation emission path. Alternatively oradditionally, the radiation source may be configured to generateradiation having an intensity that is modulated proportionally to theattenuation factor, and/or radiation with a time duration that ismodulated proportionally to the attenuation factor, and/or radiationwith an intensity that is modulated inversely proportionally to theattenuation factor, and/or radiation with a frequency that is modulatedinversely proportionally to the attenuation factor.

Another variation of a system for positioning a radiation source maycomprise a circular gantry, a radiation source mounted on the gantry,positron emission detectors mounted on the gantry, and a controller incommunication with the radiation source and the positron emissiondetectors. The positron emission detectors may be configured to detect asingle positron annihilation emission path that intersects a firstPET-avid region of interest and a second PET-avid region of interestwithin a coordinate system. The controller may be configured (e.g., byprogramming an algorithm that is stored in memory) to position theradiation source to a location along the emission path, and theradiation source may be configured (e.g., by a program stored in memoryand/or one or more signals from the controller) to generate radiationthat is adjusted according to a modulation factor that is inverselyproportional to a projection of the first PET-avid region of interest onthe location of the radiation source. In some variations, the radiationsource may be configured to generate a radiation beam with a timeduration that is modified by the modulation factor. Alternatively oradditionally, the radiation source may be configured to generateradiation with an intensity that is modified by the modulation factor.In some examples, the second PET-avid region of interest may intersectwith a third region of interest, and the first region of interest maynot intersect with the third region of interest.

One variation of a system for emission guided radiation therapy maycomprise a gantry movable about a patient area, a plurality of positronemission detectors arranged movably along the inner gantry configured todetect a plurality of positron annihilation emission paths within thepatient area, and a radiation source arranged movably along the outergantry. The gantry may comprise a rotatable inner gantry and a rotatableouter gantry, and the radiation source may be arranged movably along theouter gantry. The radiation source may be configured to apply radiationalong the plurality of positron annihilation emission paths within thepatient area, and the inner gantry may be capable of rotating at ahigher rate than the outer gantry. Optionally, the system may furthercomprise single-photon emission detectors arranged movably along theinner gantry. In some variations, the radiation source may comprise acollimator. Such a system may optionally comprise a sense mode where theplurality of positron emission detectors obstructs the radiation source,and a firing mode where the radiation source is unobstructed and is ableto apply radiation to the patient area.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is one variation of an emission guided radiation therapy systemfor aligning radiation along positron annihilation emission paths.

FIG. 1A is a conceptual depiction of an example of an EGRT method forprobabilistically applying radiation along a line of response (LOR) thatintersects both a planning target volume (PTV) and a radiation-sensitivestructure; FIG. 1B is a flowchart diagram of one example of an EGRTmethod that functions according to the depiction in FIG. 1A; and FIGS.1C to 1E depict contour plots (with uniform contour intervals) derivedfrom computer simulations using the method of FIG. 1B.

FIG. 2A is a conceptual depiction of another variation of an EGRT methodfor applying a radiation beam with a width that corresponds to a widthof a substantially perpendicular extension region of the PTV; FIG. 2B isa flowchart diagram of one method that may be used to define anextension region of the PTV; FIG. 2C is a flowchart diagram of anexemplary implementation of the method depicted in FIG. 2A.

FIG. 3A is a conceptual depiction of another EGRT method for applying aradiation beam that distinguishes between PET-avid regions within a PTVand PET-avid regions outside of a PTV; FIG. 3B is a flowchart diagram ofan exemplary implementation of the method depicted in FIG. 3A.

FIG. 4A is a conceptual depiction of another EGRT method for applying aradiation beam that corrects for attenuation along a coincident positronemission path; FIG. 4B is a flowchart diagram of an exemplaryimplementation of the method depicted in 4A.

FIG. 5A is a conceptual depiction of another EGRT method for preciselyapplying a radiation beam along a coincident positron emission path;FIG. 5B is a flowchart diagram of an exemplary implementation of themethod depicted in FIG. 5A.

FIGS. 6A to 6C are conceptual depictions of an example of an EGRT methodwhere a plurality of radiation beams are applied along a single LOR;FIG. 6D is a flowchart diagram of an exemplary implementation of themethod depicted in FIGS. 6A to 6C.

FIG. 7 is a flowchart diagram of one example of a method that uses bothEGRT techniques and intensity modulated radiation therapy (IMRT)techniques.

FIGS. 8A and 8B are conceptual depictions of an EGRT method that updatesthe location information for a tumor and/or PTV during EGRT; FIG. 8C isa flowchart diagram of an exemplary implementation of the methoddepicted in FIGS. 8A and 8B.

FIG. 9A is a conceptual depiction of another example of an EGRT methodfor modulating the radiation applied to a PTV for uniform dosedistribution; FIG. 9B is a flowchart diagram of an exemplaryimplementation of the method depicted in FIG. 9A.

FIGS. 10A and 10B are conceptual depictions of an EGRT method forcalculating the origin point of a LOR; FIG. 10C is a flowchart diagramof an exemplary implementation of the method depicted in FIG. 10A.

FIG. 11A is a conceptual depiction of one variation of an EGRT methodfor delivering radiation to a hypoxic tissue region; FIG. 11B is aflowchart diagram of an exemplary implementation of the method depictedin FIG. 11A.

FIG. 12A is a conceptual depiction of a variation of an EGRT method fordelivering radiation along a LOR that intersects a PTV with reducedpositron emission activity; FIG. 12B is a flowchart diagram of anexemplary implementation of the method depicted in FIG. 12A.

FIG. 13 is a flowchart diagram of one example of an EGRT method thatuses more than one PET tracer.

FIG. 14A is a conceptual depiction of an example of an EGRT method forapplying radiation along a LOR that intersects a plurality of PTV; FIG.14B is a flowchart diagram of an exemplary implementation of the methoddepicted in FIG. 14A.

FIG. 15A to 15B is a schematic depiction of an example of an EGRT systemwith a movable inner gantry and a separately movable outer gantry; FIG.15C is a flowchart diagram of one example of how the system depicted inFIGS. 15A and 15B may be used.

DETAILED DESCRIPTION

Described herein are systems and methods for positioning a radiationsource with respect to one or more regions of interest in a coordinatesystem. In some variations, such systems and methods may be used foremission guided radiation therapy for the delivery of radiation alongemission paths of photons from positron annihilation events. The systemsand methods described here may be used to deliver an elevated dose ofradiation to a first region of interest (e.g., tumors), while deliveringlittle, if any, radiation to a second region of interest (e.g.,peripheral tissues). The systems and methods described below may be ableto precisely locate a targeted tumor region so that an elevated level ofradiation may be applied to the tumor(s) while preserving the tissuearound the tumor(s). These systems and methods may help to provideaccurate tumor localization, and may be used to deliver radiation beamsto the target tumor region in real-time (e.g., within seconds after apositron annihilation emission path has been detected). These systemsand methods may handle and manage uncertainties originating frommultiple processes such as tumor volume delineation, patient setup andphysiologic motion in order to provide useful radiation treatment. Thesystems and methods described herein may help improve radiationtreatment efficiency, patient comfort, and/or cost effectiveness. Whilethe variations and examples described below refer to EGRT systems, itshould be understood that these are merely examples of systems that maybe used to position a radiation source with respect to one or moreregions of interest in a coordinate system. Regions of interest within acoordinate system may include, but are not limited to, tumor tissue,non-tumor tissue, radiation-sensitive organs or structures, anyanatomical structures, any regions or volumes that emit positrons (e.g.,PET-avid regions), any regions that do not emit positrons (e.g.,non-PET-avid regions), regions or volumes that may be defined withrespect to a PET-avid region, stationary regions or volumes, movingregions or volumes, any region or volume identified by a user orpractitioner (e.g., a planning target volume) or a machine algorithm(e.g., an image processing algorithm) and the like.

EGRT may be used alone or in conjunction with other types of radiationtherapies. For example, EGRT may be used with intensity modulatedradiation therapy (IMRT) and/or image guided radiation therapy (IGRT).IMRT may be capable of generating highly conformal dose distributions todeliver radiation to a targeted tumor region while sparing healthytissues. IGRT may use imaging modalities such as MRI or CT inpre-treatment planning to locate the tumor(s) within the patient.Combining either or both of these imaging modalities with EGRT may beuseful for real-time location tracking of the targeted tumor region tohelp ensure that the therapeutic radiation is directed to the intendedtissue region.

Disclosed herein are systems and methods for EGRT using a PET tracer,where radiation may be applied along a line of response (LOR) that isaligned with a detected coincident positron annihilation emission path.Systems that may be used for EGRT may comprise a gantry movable about apatient area, one or more positron emission detectors that may bemovable along the gantry, and one or more therapeutic radiation sourcesthat may also be movable along the gantry. The one or more positronemission detectors may be capable of detecting and tracking the emissionpaths corresponding to a plurality of regions of interest (e.g.,tumors). The one or more radiation sources may be configured tocompensate for the motion of each of the plurality of tumors so thatradiation may be accurately applied to the tumor(s) and not to healthytissue. One variation of a system (130) for positioning a radiationsource that may be used for emission guided radiation therapy isdepicted in FIG. 1. The system (130) may comprise a circular moveablegantry (not shown), a radiation source (131) mounted on the gantry, oneor more positron annihilation emission sensors (133) positioned atvarious locations on and around the gantry, one or more x-ray detectors(132), a motion system (134), and a controller or microprocessor (135).The x-ray detectors (132) and positron annihilation emission sensors(133) may also be mounted on the moveable gantry. In some variations,the positron emission sensors (133) and the x-ray detectors (132) may bearranged around a substantial portion of the perimeter of the gantry.The positron emission sensors (133) may be configured to detect positronannihilation events by sensing the emission paths (136) of the photonsresulting from the annihilation events. The motion system (134) may beconfigured to move the gantry and attached equipment about a region ofinterest or target volume (138) to align the radiation source (131) withthe detected emission path (136). The microprocessor (135) may beconnected to the radiation source (131), positron emission sensors(133), x-ray detectors (132) and the motion system (134) in order toregulate the motion of each of these components with respect to eachother, as well as to activate each of these components in a desiredsequence. For example, the microprocessor (135) may identify thecoincident photon emission path (136) that intersects the target volume(138), and may coordinate the alignment, configuration, and triggeringof the radiation source (131) to direct radiation to the target volume(138) along the detected emission path (136).

The microprocessor (135) may control the rotation of the gantry toadjust the position of the radiation source (131) in response to aplurality of detected emission paths in the course of an EGRT session.The microprocessor of an EGRT system may comprise a computer readablestorage medium and may be able to execute various functions inaccordance with software or firmware stored in the computer readablestorage medium. Examples of computer readable storage mediums caninclude, but are not limited to, an electronic, magnetic, optical,electromagnetic, infrared, or semiconductor system, apparatus or device,a portable computer diskette (magnetic), a random access memory (RAM)(magnetic), a read-only memory (ROM) (magnetic), an erasableprogrammable read-only memory (EPROM) (magnetic), a portable opticaldisc such a CD. CD-R, CD-RW, DVD. DVD-R, or DVD-RW, or flash memory suchas compact flash cards, secured digital cards, USB memory devices,memory sticks, and the like. The software or firmware can also bepropagated within any transport medium for use by or in connection withan instruction execution system, apparatus, or device, such as acomputer-based system, processor-containing system, or other system thatcan fetch the instructions from the instruction execution system,apparatus, or device and execute the instructions. Examples of transportmediums can include, but are not limited to, an electronic, magnetic,optical, electromagnetic or infrared wired or wireless propagationmedium.

While the systems and methods for EGRT described herein may beconfigured to detect and respond to emission paths from coincidentpositron annihilation emission events arising from PET tracers, othertypes of radioactive tracers may also be used for EGRT. For example,EGRT systems and methods may additionally or alternatively be configuredto detect and respond to single photon emissions arising from SPECTtracers. Other radioactive tracers that are commonly used in nuclearmedicine may also be used with the EGRT systems and methods describedherein. Emission rays from such radioactive tracers may serve asguidance for accurate and near real-time tumor tracking. Depending theon type of radioactive tracer that is used, EGRT systems may comprise avariety of detectors, such as positron emission detectors, single-photonemission detectors, and the like. EGRT systems may also comprise avariety of therapeutic radiation sources, including linear accelerators,radioactive materials, x-ray sources, particle beam sources, etc. Insome variations, a radiation source may comprise a collimator capable ofdelivering radiation in response to single photon events. One example ofa system that may be used for EGRT is described in U.S. Pat. No.7,265,356 filed on Nov. 29, 2004. Additional descriptions and examplesof EGRT systems are provided below, as well as in U.S. Pat. Appl. Publ.No. 2009/0256078 filed on Feb. 9, 2009, which is hereby incorporated byreference in its entirety.

Methods for EGRT may be used to track the location of tumors in realtime, and/or may be used to deliver a desired dose of radiation totumor(s) in a planning target volume (PTV) while sparing peripheraltissue. A PTV may be determined during a pre-treatment and/or planningsession by a physician and/or technician (e.g., radiation oncologist,medical physicist, radiologist, radiation therapist, etc.) using avariety of imaging modalities, such as CT, PET, MRI, x-ray, etc., eitheralone or in combination. A PTV may also be determined during a radiationtherapy session. For example, a PTV may be determined periodicallyduring a radiation therapy session using one or more types of on-boardimaging modalities (e.g., CT, PET, MRI, X-ray, etc.), either alone or incombination. Data pertaining to a PTV may be stored in themicroprocessor of an EGRT system for use by a medical physicist and/orradiation therapist during the radiation therapy session. A PTV mayinclude the tumor region and peripheral non-tumor tissue in the regionof the tumor region, or a PTV may include only the tumor region withoutthe peripheral non-tumor tissue. Alternatively or additionally, a PTVmay include the visible location and growth of a tumor as determined bya selected imaging modality (e.g., CT, PET, MRI, X-ray. SPECT, etc). Insome cases, a PTV may include a PET-avid tissue region (i.e., a tissuevolume that has taken up PET tracer and is emitting photons resultingfrom positron annihilations), and in other cases, a PTV may include boththe PET-avid region and adjacent non-PET-avid tissue regions. In somevariations, a PTV may include the regions described above with one ormore additional margins, for example, margins for patient and/or organmotion, organ shape and size variation, and uncertainties in radiationbeam alignment.

Some methods may help to compensate for tumor and/or PTV movement due torespiration or other patient movement, and/or provide for more accurateor precise tumor edge detection, and/or help to ensure that theradiation applied to a PTV is homogeneous by reducing “hot” or “cold”spots in the PTV (e.g., such that the radiation dose is uniformlydelivered across the entire PTV). While various methods for EGRT areindividually described below, it should be understood that one or moreof the methods disclosed herein may be combined before or during an EGRTsession. Optionally, one or more of these methods of EGRT may be used inconjunction with surgery, chemotherapy, brachytherapy, and/or othercancer therapies in the course of the cancer treatment of a patient.

One variation of a method for EGRT may deliver a reduced quantity ofradiation to radiation-sensitive structures while delivering aprescribed dose of radiation to a tumor located in a PTV. Certainvariations of such methods may avoid delivering any radiation to aselected tissue region or any radiation-sensitive structures. Aradiation-sensitive structure may be, for example, an organ that isparticularly prone to radiation damage. Radiation-sensitive structuresmay include the heart, esophagus, rectum, stomach, upper and lowerintestines, breast, salivary glands organs involved in gametogenesis,the spinal cord and other neural tissue, etc. In some variations ofEGRT, radiation-sensitive structures may optionally be treated with aradioprotector (e.g., amifostine), which may help theseradiation-sensitive structures self-repair any radiation damage. Onevariation of a method that delivers a reduced quantity of radiation toradiation-sensitive structures may comprise delivering radiation lessfrequently along coincident positron annihilation emission paths or LORthat intersect with the radiation-sensitive structures. FIG. 1Aconceptually depicts a patient area (100) with a planning target volumePTV (102) and a radiation-sensitive structure (104). At least a portionof the PTV (102) has taken up a PET tracer (e.g., FDG, FLT, F-MISO), andmay be emitting photons resulting from positron annihilation events.i.e., at least a portion of the PTV may be PET-avid. An emission path orline of response originating within the PTV may intersect theradiation-sensitive structure (104), such as line of response (106),while others may not intersect the radiation-sensitive structure (104),such as line of response (108). A radiation source (not shown) may applyradiation along the LOR (108) at a certain frequency and intensity todeliver a prescribed dose to the PTV (102). The radiation source mayapply radiation that has been attenuated or modulated (e.g., infrequency and/or intensity) along the LOR (106) to reduce the radiationexposure to the radiation-sensitive structure (104). For example, thefrequency with which radiation is delivered along the LOR (106) may bereduced in a probabilistic manner. Alternatively or additionally,radiation delivered along the LOR (106) may be attenuated (e.g., reducedintensity or power) as compared to the radiation delivered along the LOR(108).

One example of a method (110) of delivering a reduced quantity ofradiation to radiation-sensitive structures while delivering aprescribed dose of radiation to a PTV is diagrammatically represented inFIG. 1B. The method (110) may, for example, reduce the frequency withwhich radiation is applied along a LOR that intersects aradiation-sensitive structure. This method may be implemented using anEGRT system comprising a movable gantry, one or more positron emissiondetectors along the gantry, one or more radiation sources mounted on thegantry, a motion system, and a microprocessor. Processing a LOR (112)may comprise detecting a single coincident positron annihilationemission path using a positron emission detector, and may optionallycomprise storing data (e.g., location data, signal strength data, etc.)about the LOR in a memory of the microprocessor. Next, themicroprocessor may evaluate whether the LOR intersects a PTV (114) bycomparing the location data of the LOR with location data of the PTVstored in the memory of the microprocessor. If not, the EGRT system mayreturn to the initial state (112) to detect another LOR. If so, themicroprocessor may evaluate whether the LOR intersects aradiation-sensitive structure (116) by comparing the location data ofthe LOR with location data of the radiation-sensitive structure. If not,the microprocessor may send an instruction to a radiation source of theEGRT system to apply radiation along the LOR (122). If so, themicroprocessor may randomly generate a number X between 0 and 1 (118).The microprocessor then determines whether the number X is below apre-programmed probability threshold T (120). If not, then the EGRTsystem may return to the initial state (112) to detect another LOR. Ifthe modulation number X is below a pre-programmed threshold T, then themicroprocessor may send an instruction to the radiation source to applyradiation along the LOR (122). Once radiation has been delivered alongthe detected LOR, the method (110) may be repeated as may be desirable.e.g., until a prescribed dose of radiation has been applied to the PTVand/or the radiation-sensitive structure. As an example, it may bedesirable to prescribe dose to a radiation-sensitive structure that isno more than 20% of the dose level of the surrounding tissue and/or PTV.In this example, the probability threshold T may be selected to be 0.2,so that radiation is delivered to one out of every five lines ofresponse that intersect both the radiation-sensitive structure and thePTV. Alternatively, the probability threshold T may also represent anattenuation or scale factor by which the radiation is modulated. Forexample, the radiation that is applied along a LOR that intersects botha PTV and a radiation-sensitive structure may be modulated by theprobability threshold of T=0.2 such that the radiation applied is at 20%of the nominal intensity level. Alternatively, the nominal leaf-opentime of the radiation source may be 20% of the nominal leaf-open time.The probability threshold T may be any suitable value, for example, 0,0.005, 0.01, 0.05, 0.10, 0.5, 0.75, 0.9, 1.0 etc. In other variations,the intensity or power of the radiation applied along a LOR may beattenuated or scaled by a probabilistic coefficient. A probabilisticcoefficient may be derived from a randomly generated number between 0and 1 that is less than the threshold T.

FIGS. 1C to 1E are contour plots that represent computer-simulatedradiation dose maps when the method (110) is implemented to applyradiation to a PTV (140). The different contour plots in FIGS. 1C to 1Ehave uniform contour intervals and reflect the effect of varying theprobability threshold T on the amount of radiation applied to aradiation-sensitive structure (142). FIG. 1C depicts the dose profilewhen the probability threshold T=1.0 (i.e. no penalty to delivering doseto the radiation-sensitive structure). In this example, the radiationdose to the radiation-sensitive structure (142) is similar to theradiation dose of surrounding tissue. FIG. 1D depicts the dose profilewhen the probability threshold T=0.2, and FIG. 1E depicts the doseprofile when the probability threshold T=0.0. As the probabilitythreshold T decreases towards zero, the total dose to theradiation-sensitive structure (142) may decrease as depicted in thecontour maps.

In other variations of EGRT methods, the radiation source may adjust theproperties of the radiation beam delivered to the PTV to deliverradiation to non-PET-avid tissue within the PTV. For example, the widthof the radiation beam may be expanded to deliver radiation tonon-PET-avid tissue within the PTV, and/or multiple radiation beams maybe applied over time at non-PET-avid locations within the PTV. Oneexample of such a method is conceptually depicted in FIG. 2A. Thismethod may comprise acquiring images (e.g., one or more of CT. MRI, PET,etc., including PET-CT images) during a treatment planning phase todefine the planning target volume or volumes to be treated during EGRT.The margin extended PTV (202) may extend with a width (W1) from the edgeof the PET-avid target volume (204). During an EGRT session, when a LOR(206) that intersects the PTV (202) is detected by a positron emissiondetector (not shown), a radiation beam (208) applied by the radiationsource (210) may be adjusted so that the radiation beam width (W2) iswider in the direction of added margin between the PET-avid volume (204)and PTV (202). In some variations, the width (W2) of the radiation beammay be extended in the direction of the margin if the radiation beam(208) is substantially perpendicular to the margin extension direction.

One example of a method that applies radiation to tissue adjacent to theboundaries of a PET-avid volume within a PTV is depicted in FIGS. 2B and2C. FIG. 2B depicts a method (220) that may be used during treatmentplanning, which may take place prior to the EGRT session, or may takeplace during the EGRT session. The method (220) may comprise acquiring(222) one or more images, such as CT, MRI, PET and/or composite PET-CTimages. Based on the image(s) acquired, the PTV(s) may be defined (224)by locating a PET-avid region. Optionally, any extension margins beyondthe PET-avid volume(s) may also be defined, e.g., PTV(s) may comprise aPET-avid tissue and non-PET-avid tissue adjacent to the PET-avid tissue.In some variations, the treatment volume(s) and/or extension marginsbeyond the PET-avid volume may be defined by additional patient data,computer-executed image processing algorithms, and/or practitionerinput, and may have a length and or width beyond the edge of thePET-avid volume(s). Information about the PET-avid volume and/orextension margins (e.g., the length, width, volume, orientation of themargin extension with respect to the target volume, etc.) that define aborder of a PTV may be stored in a memory of a microprocessor of an EGRTsystem for use during the treatment session.

FIG. 2C depicts one example of an EGRT method (230) that may use theinformation from the method (220) to provide radiation treatment to apatient. This method may be implemented using an EGRT system asdescribed above and further described below. The imaged PET-avid volume,and margin extension data (e.g., the length, width, volume, orientationof the margin extension with respect to the target volume, etc.) fromthe method (220) may be stored in a memory of a microprocessor of theEGRT system prior to the EGRT session. Alternatively or additionally,extension margins may be determined or computed by the EGRT system atany point during the session by acquiring one or more images duringtreatment, such as CT, MRI, PET and/or composite PET-CT images.Processing a LOR (232) may comprise detecting a single coincidentpositron annihilation emission path using a positron emission detector,and may optionally comprise storing data about the LOR (e.g., locationdata, signal strength data, etc.) in a memory of the microprocessor.Next, the microprocessor may evaluate whether the LOR intersects a PTV(234) by comparing the location data of the LOR and location data of thePTV. If not, the EGRT system may return to the initial state (232) todetect another LOR. If so, the microprocessor may use the data from themethod (220) to compute (236) whether the LOR is substantiallyperpendicular to the margin extension direction. If not, themicroprocessor may send an instruction to a radiation source of the EGRTsystem to apply radiation along the LOR (268). If the LOR is computed tobe substantially perpendicular to the margin extension direction, themicroprocessor may send an instruction to the radiation source todeliver (240) a radiation beam along the LOR, where the radiation beamhas a width that corresponds to a width of the extension margin. In somevariations, the extension margin may be computed by a microprocessor ofthe EGRT system during the session, and may be used alone or inconjunction with any extension margins that may have been determinedduring a treatment planning phase. Once radiation has been deliveredalong the LOR, the method (230) may be repeated as may be desirable,e.g., until a prescribed dose of radiation has been applied to the PTV.

Some variations of EGRT methods may distinguish between coincidentpositron annihilation emission paths that originate from a planningtarget volume and emission paths that originate outside of the planningtarget volume. Positron annihilation events may take place outside of aPTV, and increased uptake of certain PET-tracers such as FDG may occur,for instance, in the heart, brain, areas of inflammation, infected areasof the lung, or other anatomical regions. For example, the PET tracermay be taken up by tissues in a plurality of locations, and EGRT may beplanned for only a subset of those locations (i.e., some PET-avidtissues may be suitable targets for radiation while other PET-avidtissues may not). FIG. 3A depicts a patient area (300) that has a firstPET-avid volume (302) and a second PET-avid volume (304). In thisexample, the first PET-avid volume (302) may not be part of a PTV. Thesecond PET-avid volume (304) may be located within a PTV. An EGRT methodthat does not distinguish between coincident positron annihilationemission paths that originate from within a PTV and emission paths thatoriginate outside of the PTV may apply an increased radiation dose inthe directions connecting the PTV with the PET-avid regions outside ofthe PTV. One way in which an EGRT method may avoid creating localizedregions of relatively higher radiation may comprise computing amathematical projection of PET-avid volumes outside of the PTV for eachposition that a therapeutic radiation source may occupy. For example,the first PET-avid volume (302) may have a projection (306) for aradiation source at location (307). Similar projections of PET-avidvolumes outside of a PTV may be computed for one or more of theradiation source locations on a gantry of an EGRT system. In somevariations, the computed projections may be used to modulate the time orintensity or number of firings of the radiation delivered along eachpath that is inversely proportional to the value of the projection at aparticular location. For example, a PET-avid region outside of the PTVmay result in a higher relative projection value along a path throughthe PTV as compared to a different path through the PTV. The radiationsource may deliver radiation in accordance with a computed projectionvalue. For example, an increased projection value at a certain locationof the gantry may signal the therapeutic radiation source to deliverproportionally less radiation from that location than a reducedprojection value would. The radiation delivered may be modulated invarious ways, for example, in time, intensity, or number of firingsalong the emission path.

One example of a method (310) of avoiding the creation of localizedregions of high radiation is diagrammatically represented in FIG. 3B.The method (310) modulates the radiation that is applied along a LORaccording to the projection of a “hot spot” at the location of theradiation source. This method may be implemented using an EGRT systemcomprising a movable gantry, one or more positron emission detectorsalong the gantry, one or more radiation sources along the gantry, amotion system, and a microprocessor. Processing a LOR (312) may comprisedetecting a single coincident positron annihilation emission path usinga positron emission detector, and may optionally comprise storing dataabout the LOR (e.g., location data, signal strength data, etc.) in amemory of the microprocessor. Next, the microprocessor may evaluatewhether the LOR intersects a PTV (314) by comparing the location data ofthe LOR with location data of the PTV that may be stored in themicroprocessor memory. If not, the EGRT system may return to the initialstate (312) to detect another LOR. If so, the microprocessor may computea modulation factor that is inversely proportional to the projection ofone or more PET-avid regions that are not in the PTV (316). The computedmodulation factor may be used to adjust the frequency, duty cycle,intensity, number of firings, and/or other characteristics of theradiation beam. The microprocessor may then provide an instruction tothe radiation source to modulate the radiation beam according to themodulation factor. The radiation source may then deliver (318) themodulated radiation along the LOR. Once radiation has been deliveredalong the detected LOR, the method (310) may be repeated as may bedesirable, e.g., until a prescribed dose of radiation has been appliedto the PTV.

Some methods for EGRT may compensate for any attenuation of LOR signalstrength that may occur due to density variations within the subject.FIG. 4A conceptually depicts a patient area (400) with a PET-avid volume(401) and areas of higher density. Areas of increased density may be dueto the presence of prosthetic implants, organs with higher tissuedensity, such as bones (404), and the like. For example, a LOR (402)that intersects the bone structures (404) may be more attenuated than aLOR (406) that does not intersect any bones or areas of increaseddensity. Various imaging modalities may be used to approximate theattenuation of the signal strength of a LOR. In some variations of EGRT,kilovoltage CT images may be used to estimate and compensate for theattenuation of the LOR signals. The LOR attenuation may also be computedbased on other imaging modalities, such as cone-beam CT, MRI, X-ray,etc. Estimation of the attenuation of LOR signals may be performed in aplanning phase or pre-treatment session or during the radiotherapytreatment session. In some variations, the attenuation of the LORsignals may be dynamically computed during the radiotherapy treatmentsession using PET or x-ray imaging techniques. The radiation beam maythen be adjusted according to the attenuation of the LOR signals tocompensate for LOR signal attenuation so that the correct amount ofradiation is delivered to the PTV while limiting radiation to healthytissue. In some cases, it may be desirable to apply an increased levelof radiation along an attenuated LOR to compensate for the attenuationeffect and to help ensure that the PTV receives a therapeuticallyeffective level of radiation. In other cases, where the area of higherdensity that attenuates the LOR is a radiation-sensitive structure, itmay be desirable to apply a reduced level of radiation along that LOR toreduce or limit the radiation delivered to the higher density region.For instance, a bone structure may attenuate a LOR signal, and theradiation applied along the attenuated LOR may be reduced to limit theradiation delivered to the bone structure. The radiation beam may bemodulated by, for example, increasing or decreasing in magnitude orfrequency to compensate for the attenuation of magnitude or frequency ofthe detected LOR signal. Alternatively or additionally, the radiationbeam may be modulated in time (e.g., duty cycle) and/or intensity. Thismodulation may be implemented by calculating the density projection of aLOR along its total path through the patient, converting that projectionestimate to LOR photon energies (i.e. 511 keV), and adjusting the timeor intensity of the radiation response so that the amount of radiationdelivered compensates for the total attenuation along the LOR path.

One example of a method (410) of correcting or compensating for LORsignal attenuation so that a sufficient quantity of radiation is appliedto the PTV is diagrammatically represented in FIG. 4B. The method (410)modulates the radiation that is applied along a LOR that compensates forthe attenuation measured in the LOR signal. This method may beimplemented using an EGRT system comprising a movable gantry, one ormore positron emission detectors along the gantry, one or more radiationsources along the gantry, a motion system, and a microprocessor.Processing a LOR (412) may comprise detecting a single coincidentpositron annihilation emission path using a positron emission detector,and may optionally comprise storing data about the LOR (e.g., locationdata, signal strength data, etc.) in a memory of the microprocessor.Next, the microprocessor may evaluate whether the LOR intersects a PTV(414) by comparing the location data of the LOR with location data ofthe PTV that may be stored in the microprocessor memory. If not, theEGRT system may return to the initial state (412) to detect another LOR.If so, the microprocessor may compute (416) the LOR attenuation based ona kilovoltage or megavoltage CT image that may be previously enteredand/or stored in a memory of the microprocessor. The attenuation of theLOR signal may be used to compute an attenuation value (418) that may beused to modulate the radiation beam. In some variations, the computedattenuation value may adjust the radiation therapy average energy bydecreasing or increasing the radiation amount proportionally to theamount of LOR signal attenuation so that the correct amount of radiationis delivered along the attenuated LOR. The microprocessor may thenprovide an instruction to the radiation source to modulate the radiationbeam according to the computed attenuation value. For example, theradiation beam may be modulated proportionally or inverselyproportionally to the attenuation factor. The radiation source may thendeliver (420) the modulated radiation along the LOR. Once radiation hasbeen delivered along the detected LOR, the method (410) may be repeatedas may be desirable, e.g., until a prescribed dose of radiation has beenapplied to the PTV.

One variation of a method that may be used with an EGRT system may beused for delivering radiation to a plurality of planning target volumes.The method may comprise detecting positron emission activity frommultiple planning target volumes, and then applying one or moreradiation beams along each detected LOR that intersects at least one ofthe planning target volumes. The EGRT system and this method may be ableto compensate for any movement of each of the planning target volumes,regardless of the correlation of their movement, by responding to theLOR in near real-time (e.g., within seconds after a LOR has beendetected). For example, a radiation beam may be applied along a detectedLOR in less than 5 s, 4 s, 3 s, 2 s, 1 s, or 0.5 s, after the LOR hasbeen detected. FIG. 14A depicts one example where a patient area (1400)has a first PET-avid region (1402) moving along arrow (1404) within afirst PTV and a second PET-avid region (1406) moving along arrow (1408)within a second PTV. The movement of the first and second PET-avidvolumes may be correlated or uncorrelated. LOR (1410), (1412) and (1414)represent LOR that intersect at least one of the planning targetvolumes. An EGRT system may apply one or more radiation beams along LOR(1410) to the first PET-avid region (1402), and/or apply radiation beamsalong LOR (1412) to the second PET-avid region (1406), and/or applyradiation beams along the LOR (1414) to both the first and secondPET-avid regions to deliver a prescribed dose of radiation to the firstand second PET-avid regions.

One example of a method (1420) for delivering radiation to a pluralityof planning target volumes is diagrammatically represented in FIG. 14B.This method may be implemented using an EGRT system comprising a movablegantry, one or more positron emission detectors along the gantry, one ormore radiation sources along the gantry, a motion system, and amicroprocessor. Processing a LOR (1422) may comprise detecting a singlecoincident positron annihilation emission path using a positron emissiondetector, and may optionally comprise storing data about the LOR (e.g.,location data, signal strength data, etc.) in a memory of themicroprocessor. Next, the microprocessor may evaluate whether the LORintersects a first PTV (1424) by comparing the location data of the LORwith location data of the first PTV. If so, then the microprocessor maysend an instruction to the radiation source to apply radiation along theLOR (1428). If the LOR does not intersect a first PTV, themicroprocessor may evaluate whether the LOR intersects a second PTV(1426) by comparing the location data of the LOR with location data ofthe second PTV. If so, then the microprocessor may send an instructionto the radiation source to apply radiation along the LOR (1428). If not,then the EGRT system may return to the initial state (1422) to detectanother LOR. Once radiation has been delivered along the detected LOR,the method (1420) may be repeated as may be desirable, e.g., until aprescribed dose of radiation has been applied to the first and/or secondplanning target volumes.

Some variations of EGRT methods may be used to help the therapeuticradiation source to precisely direct radiation beams towards the PTV.One example of such a method is conceptually depicted in FIG. 5A, wherea patient represented by patient area (500) is located within a centralportion of a gantry (502) of an EGRT system. An LOR (503) that isdetected by a positron emission detector may first be evaluated todetermine whether the LOR (503) intersects with a PTV (504). In somecircumstances, a radiation source (506) may fire a radiation beam (508)when it is positioned a finite distance away from the detected LOR. Theradiation beam (508) may be directed at a specific point (507) in thePTV (504), which may help to align the LOR (504) and the radiation beam(508). The point (507) may be the midpoint of a line segment formed bythe intersection of the LOR with the PTV. For example, the point (507)may be computed by identifying a first point where the LOR crosses theboundary of a PTV, identifying a second point where the LOR crosses theboundary of the PTV at a second location of the boundary, connecting thefirst and second points to define a line segment. The point (507) may bethe midpoint of the defined line segment. Alternatively, the point (507)may be at any another location within the PTV.

One example of a method (510) of precisely directing a radiation beam ata particular location in a PTV is diagrammatically represented in FIG.5B. The method (510) directs the radiation source to apply a radiationbeam at the midpoint of a line segment formed by the intersection of theLOR with the PTV. This method may be implemented using an EGRT systemcomprising a movable gantry, one or more positron emission detectorsalong the gantry, one or more radiation sources along the gantry, amotion system, and a microprocessor. Processing a LOR (512) may comprisedetecting a single coincident positron annihilation emission path usinga positron emission detector, and may optionally comprise storing dataabout the LOR (e.g., location data, signal strength data, etc.) in amemory of the microprocessor. Next, the microprocessor may evaluatewhether the LOR intersects a PTV (514) by comparing location data of theLOR with location data of the PTV. If not, the EGRT system may return tothe initial state (512) to detect another LOR. If so, the microprocessormay compute (516) the midpoint of the line segment formed by theintersection of the LOR with the PTV. The microprocessor may thenprovide an instruction to the radiation source to direct and apply (518)a radiation beam toward the midpoint computed in the previous step. Onceradiation has been delivered along the detected LOR, the method (510)may be repeated as may be desirable, e.g., until a prescribed dose ofradiation has been applied to the PTV.

Other variations of EGRT methods may comprise delivering radiation inresponse to a single LOR from multiple locations and/or at multiplepoints in time. As an example, a radiation beam may be delivered along aLOR from either end of the LOR, or at different times from the same LORendpoint. FIGS. 6A and 6B conceptually depict one example of howmultiple radiation beams may be applied along a LOR. FIG. 6A depicts apatient (600) located in a gantry (602) with a PET-avid region of a PTV(604). A LOR (606) originating from within the PTV (604) may be detectedat a first location (608) and a second location (610) along the gantry(602). A radiation source (612) may be moved along the gantry at variouspositions to apply a radiation beam along the LOR (606) to the PTV(604). For example, as depicted in FIG. 6B, the radiation source (612)may be moved to the first location (608) to apply a first radiation beam(614) along the LOR (606) to the PTV (604). Additionally oralternatively, as depicted in FIG. 6C, the radiation source (612) may bemoved to the second location (610) to apply a second radiation beam(616) along the LOR (606) to the PTV (604). In some variations, aplurality of radiation beams may be applied from the radiation source(612) along the LOR (606) located at a single position.

One example of a method (620) of precisely directing a radiation beam ata particular location in a PTV is diagrammatically represented in FIG.6D. The method (620) directs the radiation source to apply a radiationbeam from one or more endpoints of a detected LOR. This method may beimplemented using an EGRT system comprising a movable gantry, one ormore positron emission detectors along the gantry, one or more radiationsources along the gantry, a motion system, and a microprocessor.Processing a LOR (622) may comprise detecting a single coincidentpositron annihilation emission path using a positron emission detector,and may optionally comprise storing data about the LOR (e.g., locationdata, signal strength data, etc.) in a memory of the microprocessor.Next, the microprocessor may evaluate whether the LOR intersects a PTV(624) by comparing location data of the LOR with location data of thePTV. If not, the EGRT system may return to the initial state (622) todetect another LOR. If so, the microprocessor may provide an instructionto the radiation source to deliver (626) a first radiation beam alongthe LOR from a first location. The microprocessor may then provide aninstruction to the radiation source to apply (628) a second radiationbeam along the LOR from a second location. Optionally, a plurality ofradiation beams may be delivered along the LOR from the same location.Once radiation has been delivered along the detected LOR, the method(620) may be repeated as may be desirable, e.g., until a prescribed doseof radiation has been applied to the PTV.

Another variation of a method may combine intensity modulatedradiotherapy (IMRT) and EGRT to deliver radiation treatment to aplanning target volume. A hybrid IMRT-EGRT method may be useful if thecoincident positron annihilation emission signal is low, or if shortertreatment time is desired. In some variations, IMRT and EGRT may haveseparate pre-treatment plans, and during the radiation therapy, IMRT maybe used to deliver radiation beams for one portion of the session, whileEGRT may be used to deliver radiation beams for another portion of thesession. For example, the radiation beam may be applied using IMRT firstand EGRT second (or vice versa) for each position of the radiationsource along the gantry. Some methods may alternate between IMRT andEGRT for one or more radiation source positions during the radiationtherapy session.

One example of a hybrid IMRT-EGRT method (700) is diagrammaticallyrepresented in FIG. 7. The method (700) may utilize both IMRT and EGRTtechniques to apply radiation to a PTV. The method (700) may beimplemented using an EGRT system comprising a movable gantry, one ormore positron emission detectors along the gantry, one or more radiationsources along the gantry, a motion system, and a microprocessor. Theradiation source may be moved to a first location along the gantry, at acertain gantry angle (702). In some variations, the set of gantry anglesmay be uniformly spaced around a circular gantry, while in othervariations, the spacing of the gantry angles may not be uniform. At eachgantry angle location, the microprocessor may receive data regarding aplurality of LOR from the positron emission detector(s) (e.g., locationdata, signal strength data, etc.), and may compute (704) or calculatebased on a pre-programmed or pre-determined model stored in themicroprocessor whether IMRT or EGRT should be used to deliver radiationto the PTV (706). This determination may be based on whether there aresufficient LOR data to respond to using EGRT. If IMRT is selected, thenthe microprocessor may provide an instruction to the radiation source todeliver (708) radiation to the entire PTV. If EGRT is selected, themicroprocessor may evaluate whether the LOR intersects a PTV (710). Ifnot, the EGRT system may return to the initial state (702) to treat thenext gantry angle. If so, the microprocessor may provide an instructionto the radiation source to deliver (712) a radiation beam along the LOR.Once radiation has been delivered using IMRT or EGRT, the radiationsource may be moved to another location, and the method (700) may berepeated as may be desirable, e.g., until a prescribed dose of radiationhas been applied to the PTV.

In another variation of a method for EGRT, the method may comprise stepsthat update the location and/or orientation of the PTV during thetreatment session. For example, the centroid of the PTV may be redefinedto account for any tumor movement that may occur during the treatment(e.g., due to a change in the patient's breathing pattern, organdeformation, peristalsis, or a shift in the patient's position, etc.).FIGS. 8A and 8B conceptually depict a patient area (800) with a PTV(802) at an initial position and a tumor (804) at an initial position inthe PTV (802). The initial positions of the PTV and tumor may bemeasured in a pre-treatment session or at an earlier point in timeduring the radiotherapy session. In the course of radiation therapy, theposition of the PTV may need to be shifted, for example, to the positiondepicted in FIG. 8B. As illustrated there, the PTV may be redefined to asecond position (806) to reflect the tumor's (808) new range of motion.In some examples, the centroid of the PTV may be redefined according toan average range of motion of the tumor. Additionally or alternatively,PET images may be reconstructed based on the PET signal data in aprevious time interval (e.g., the last 0.5 s, 1 s, 2 s, 10 s, 20 s, 50s, 60 s, 90 s, etc.) and used to transform (translate, rotate, reorient,stretch or shrink, etc.) the PTV. Some EGRT methods may comprise a stepto redefine the PTV centroid based on a change in the centroid of thetemporally-blurred reconstructed PET image relative to the baseline scanor relative to the last reconstructed PET image.

One example of an EGRT method (810) that periodically updates theposition of the PTV is depicted in FIG. 8C. The method (810) may updatethe position of the PTV every 30 seconds, but it should be understoodthat any update period may be selected as desired (e.g., 0.5 s, 1 s, 2s, 10 s, 20 s, 50 s, 60 s, 90 s, etc.). The method (810) may beimplemented using an EGRT system comprising a movable gantry, one ormore positron emission detectors along the gantry, one or more radiationsources along the gantry, a motion system, and a microprocessor. Afterthe start of the EGRT treatment (812), the microprocessor mayreconstruct (814) an initial or new PET image based on pre-treatmentdata or recent positron annihilation emission data from the last 30seconds. The PET data and/or image may be stored in a memory of themicroprocessor. The microprocessor may then determine (816) whether thecurrent position of the PTV has changed from the previous position ofthe PTV by comparing location data of the current position of the PTVwith location data of the previous position of the PTV. If not, themicroprocessor may provide an instruction to the radiation source toapply a radiation beam along a detected LOR, as previously described,and EGRT may then resume (818). If so, the PTV position may be updated(820) in the memory of the microprocessor. The microprocessor may thenuse the updated PTV location information to determine whether detectedthe LOR are located within the updated PTV. EGRT may resume (818). Onceradiation has been delivered along the LOR the method (810) may berepeated as may be desirable. e.g., until a prescribed dose of radiationhas been applied to the PTV.

Some variations of EGRT methods may be used to reduce or avoid thepeaking of a radiation dose that may occur in the center of an otherwiseuniformly PET-avid volume (i.e., “backprojection effect”). This effectmay occur because LOR that intersect the volume near the center of thePET-avid volume may be detected more frequently than those thatintersect towards the edge of the volume. An EGRT method may use afiltered-backprojection technique to reduce or eliminate radiation peaksin a PET-avid region. FIG. 9A conceptually depicts one method that maybe used to compute a one-dimensional mathematical projection (902) of aPET-avid volume (900) that may emit photons in a generally uniformdensity, and where the projection (902) is calculated by counting thenumber of coincident positron annihilation emissions that intersect acertain position of the radiation source. The calculated mathematicalprojection (902) may be mathematically filtered with a filter (904) thatis appropriate for use in a filtered-backprojection algorithm, forexample, a Ram-Lak filter, a Shepp-Logan filter, or any other filterthat may be used for image-reconstruction. The result of the filteredprojection may result in negative values which can be rectified, e.g.,set to zero, to obtain a post-filtered projection (906). Thepost-filtered projection (906) may then be used to modulate theradiation beam so that a more uniform application of radiation energy tothe PET-avid volume is delivered. For example, the intensity of thedelivered radiation, and/or the temporal aspect of the deliveredradiation, may be proportional to the post-filtered projection (906).

One example of an EGRT method (910) that may be used to apply radiationthat reduces or eliminates radiation peaks in a PET-avid region isdepicted in FIG. 9B. This method may be implemented using an EGRT systemcomprising a movable gantry, one or more positron emission detectorsalong the gantry, one or more radiation sources along the gantry, amotion system, and a microprocessor. Processing a LOR (912) may comprisedetecting a single coincident positron annihilation emission path usinga positron emission detector, and may optionally comprise storing dataabout the LOR (e.g., location data, signal strength data, etc.) in amemory of the microprocessor. Next, the microprocessor may evaluatewhether the LOR intersects a PTV (914). If not, the EGRT system mayreturn to the initial state (912) to detect another LOR. If so, themicroprocessor calculates (916) the degree to which the radiationresponse to the LOR should be modulated. The microprocessor may computea dose distribution as described in FIG. 9A, and modulate the radiationresponse based on a Ram-Lak filtered PTV projection, with negativevalues rectified to zero. The microprocessor may then provide aninstruction to the radiation source to modulate the radiation beamaccording to the post-filtered projection. The radiation source may thendeliver (918) the modulated radiation along the LOR. Once radiation hasbeen delivered along the detected LOR, the method (910) may be repeatedas may be desirable, e.g., until a prescribed dose of radiation has beenapplied to the PTV.

Another method that may be used in EGRT may deliver a radiation dosethat is proportional to the real-time or near real-time measuredintensity of the positron emitting distribution or a photon emittingdistribution across the patient volume to be treated. Such a method maybe used with an EGRT system having positron emission and/orsingle-photon emission detectors to detect emission paths, and aradiation source with a collimator to shape the radiation beam appliedto the PTV. The distribution of coincident positron annihilationemission and/or SPECT signals may be correlated with areas of hypoxia,increased cellular proliferation, or other biological or functionalaspects of a patient volume to be treated. For example, as depicted inFIG. 11A, at a particular time (T1), a tumor (1100) may have asub-region (1102) at a first location that may demonstrate an increasedrate of radiotracer uptake. The tumor and/or the sub-region may movesuch that the sub-region (1104) at a time (T2) may be at a secondlocation in the tumor (1100). In some cases, it may be desirable toescalate the radiation dose to these sub-regions of the patient volume,which may involve tracking the motion of these sub-regions. Somevariations of this method may use one or more PET tracers such as FDG,F-MISO. FLT, F-ACBC, Cu-ATSM, etc., as well as one or more SPECT tracerssuch as Tc-99m-tagged compounds, 99mTc-HL91, 111In-Capromab pendetide,etc., which may provide additional information about biological andfunctional makeup throughout the PTV.

One example of an EGRT method (1110) that delivers radiation to the PTVthat is proportional to the SPECT and/or coincident positronannihilation emission signal(s) from the PTV is depicted in FIG. 11B.This method may be implemented using an EGRT system comprising a movablegantry, one or more single-photon/positron emission detectors along thegantry, one or more radiation sources along the gantry, a motion system,and a microprocessor. A SPECT or PET tracer may be injected (1112) intoa patient. Examples of PET tracers that may be injected include F-MISO,FLT, FDG, etc. Examples of SPECT tracers that may be injected includeTc-99m-tagged compounds, 99mTc-HL91, 111In-Capromab pendetide(ProstaScint). After a sufficient period of time has elapsed (1114) inaccordance with the pharmacodynamics for the SPECT or PET tracer, EGRTmay commence (1116), as described above.

The method depicted in FIG. 11B may also be performed using SPECTtracers. An EGRT system may comprise single-photon emission detectors tocapture single photons emitted from the target volume. The radiationsource may then be instructed by the microprocessor to apply radiationalong the linear path of the single photon emission. The microprocessormay also discriminate between energy levels of the detected photon andmodulate the level of radiation applied along the linear path of thedetected photon according to the energy of the photon. In the case ofPET tracers, one example of EGRT may use positron emission detectors tocapture LOR emissions generated from multiple PET tracers that arewithin the target volume. The microprocessor will instruct the radiationsource to apply radiation along detected LOR intersecting with theplanning target volume.

In some circumstances, the PTV may have a lower LOR signal than thetissue immediately surrounding it. In such conditions, radiation beammay instead be directed to a “cold spot,” which may be a region oftissue that have a lower number of detected LOR than the average ratefor the surrounding tissue. A “cold spot” may be detected from aprevious PET scan or by reconstructing an image using PET dataaccumulated over certain time intervals, (e.g., 0.5 s, 1 s, 5 s, 20 s,30 s, 90 s before applying the radiation beam) and using thereconstructed image to determine the “cold spot” region. FIG. 12Aschematically depicts a planning target volume (1200) with a “cold spot”(1202), i.e., a region of tissue in the PTV with reduced coincidentpositron annihilation emission activity. Examples of “cold spot” tissuesmay include a region in the brain with hypo-intense FDG uptake or areasusing PET tracers that detect cell apoptosis, such as 18F-ML-10. A lowerdensity of LOR may be detected along the direction (1204), while ahigher density of LOR may be detected along the direction (1206). AnEGRT system may be programmed to deliver more radiation along thedirection (1204) to treat the tissue within the “cold spot” (1202).

One example of a method that may be used with an EGRT system to applyradiation to a region of tissue with low LOR activity is represented inFIG. 12B. This method may be implemented using an EGRT system comprisinga movable gantry, one or more positron emission detectors along thegantry, one or more radiation sources along the gantry, a motion system,and a microprocessor. A radiation source may be positioned at a certainlocation on the gantry (1212). The microprocessor may use data collectedfrom the one or more positron emission detectors to calculate (1214) aPET volume LOR projection at the location of the radiation source. Themicroprocessor then compares (1216) the LOR counts with a pre-determinedthreshold, which may be determined from a previously stored image, suchas a prior PET scan image, or by reconstructing an image using PET dataaccumulated over a prior time interval. If the LOR counts are above thepre-determined threshold, the microprocessor does not issue aninstruction to fire a radiation beam, and the EGRT system may return tothe initial state (1212) to process the LOR projection at another gantrylocation. If the LOR counts are below the pre-determined threshold, themicroprocessor may evaluate whether the direction(s) of the LORintersect the PTV (1218). If the direction(s) of the LOR do notintersect the PTV, the microprocessor does not issue an instruction tofire a radiation beam, and the EGRT system may return to the initialstate (1212) to process the LOR projection at another gantry location.If the direction(s) of the LOR intersect with the PTV, themicroprocessor may provide an instruction to the radiation source todeliver (1220) radiation along the direction(s) where the LOR counts arebelow the pre-determined threshold. The method depicted in FIG. 12B mayalso be performed using SPECT tracers and an EGRT system comprisingsingle-photon emission detectors.

Optionally, any of the methods above may use multiple radioactivetracers at once, such as PET or SPECT radiotracers. For example, apatient may be injected with a cocktail of FDG and FLT, or any otherdesired combination radioactive tracers. The EGRT system may beconfigured to apply a radiation beam along any detected LOR thatintersects with the PTV, regardless of which type of tracer originatedthe decay event.

One method (1300) in which multiple PET tracers may be used with any ofthe EGRT methods described herein is depicted in FIG. 13. This methodmay be implemented using an EGRT system comprising a movable gantry, oneor more positron emission detectors along the gantry, one or moreradiation sources along the gantry, a motion system, and amicroprocessor. A first tracer (e.g., FDG) may be injected (1302) into apatient. Subsequently or simultaneously, a second tracer (e.g., FLT) maybe injected (1304) into the patient. After a sufficient period of timehas elapsed (1306) in accordance with the pharmacodynamics for the firstand second tracers. EGRT may commence (1308), as previously described.

Additionally, any of the methods described above may be used incombination with a fiducial marker, radiopaque marker, or any otheridentifier that allows the PTV to be tracked for radiation therapy. Insome variations, the methods described herein may be used in combinationwith surgery and/or chemotherapy, as may be appropriate.

Optionally, any of the methods described above may use thetime-of-flight (TOF) method to evaluate whether the origin of a positronannihilation emission is within, or sufficiently close to, a planningtarget volume. The TOF method may be used with a PET system to helpimprove diagnostic PET image quality by calculating the time differencebetween the detection of each endpoint of a single LOR (i.e. the timedifference between the detection of each of the coincident positronannihilation emission photons). Using information obtained from the TOFmethod, a microprocessor may estimate or computer the origin point ofthe positron emission along the LOR path. For example, a method with anestimation error of the origin point on the order of 5 cm may triggerthe system to exclude LOR events whose calculated positron emissionorigin points are greater than this error (e.g. 5 cm) from the PTVboundary. FIGS. 10A and 10B conceptually depict how the TOF method maybe used with any of the EGRT systems and methods described above. Apatient (1002) located within a gantry (1000) may have a PTV (1004). TheEGRT system may detect a LOR (1006), and the microprocessor of the EGRTmay use the TOF method to evaluate whether the origin point of the LORis within, or sufficiently close to, the PTV. For example, in FIG. 10A,the calculated origin point (1008) of a LOR (1006) is shown. Since theorigin point (1008) does not co-localize with the PTV (1004), and is notsufficiently close to the PTV (1004), the microprocessor may beprogrammed to disregard the LOR (1006), return to a state to process anew LOR. Another example depicted in FIG. 10B depicts an example wherethe calculated origin point (1009) of the LOR (1007) is sufficientlyclose to the PTV, and the microprocessor may be programmed to provide aninstruction to the radiation source to apply radiation along the LOR(1007). Including the TOF method in combination with any of the EGRTsystems described above may help to improve EGRT performance byexcluding events that did not originate from within, or are sufficientlyclose to, the PTV.

One example of the TOF method (1010) that may be used with any of theEGRT methods described above is depicted in FIG. 10C. This method may beimplemented using an EGRT system comprising a movable gantry, one ormore positron emission detectors along the gantry, one or more radiationsources along the gantry, a motion system, and a microprocessor.Processing a LOR (1012) may comprise detecting a single coincidentpositron annihilation emission path using a positron emission detector,and may optionally comprise storing data about the LOR (e.g., locationdata, signal strength data, etc.) in a memory of the microprocessor.Next, the microprocessor may evaluate whether the LOR intersects a PTV(1014) by comparing location data of the LOR with location data of thePTV. If not, the EGRT system may return to the initial state (1012) todetect another LOR. If so, the microprocessor uses the TOF method tocomputer the positron emission origin point (1016). Based on thelocation of the origin point with respect to the PTV, the microprocessormay then evaluate whether the origin point is sufficiently close to thePTV (1018). If not, then the EGRT system may return to the initial state(1012) to detect another LOR. If so, then the microprocessor may thenprovide an instruction to the radiation source to deliver (1020)radiation along the LOR. Once radiation has been delivered along thedetected LOR, the method (1010) may be repeated as may be desirable,e.g., until a prescribed dose of radiation has been applied to the PTV.

As indicated previously, any of the above methods may be performed usingany suitable EGRT system, for example, such as the EGRT systemsdescribed in U.S. Pat. Appl. Publ. No. 2009/0256078 filed on Feb. 9,2009, which was previously incorporated by reference in its entirety.Another variation of an EGRT system that combines PET with radiotherapymay comprise a gantry having an inner gantry and an outer gantry thatare each separately rotatable. One or more positron emission detectorsmay be located on the inner gantry, while one or more radiation sourcesmay be located on the outer gantry. The inner gantry may rotate at afaster rate than the outer gantry. In some variations, the inner gantrywith the positron emission detectors may rotate faster than the outergantry with the radiation source because the positron emission detectorsmay weigh less than the radiation source. Alternatively or additionally,the inner and outer gantries may each be supported by motor systems withdifferent power outputs, where each of the motor systems may beindependently controlled. FIGS. 15A and 15B depict one example of anEGRT system (1500). The inner gantry (1502) has two positron emissiondetectors (1505) located 180 degrees across from each other. The outergantry (1504) has a radiation source (1506) configured to respond to aLOR (1508) that intersects a PTV (1510). The EGRT system may have afirst mode (e.g., “sense” mode) where the EGRT system detects one ormore LOR, and a second mode (e.g., “fire” mode) where the EGRT appliesradiation along the detected LOR that intersects the PTV (1510). In thesense mode, the positron emission detectors may occlude the subject fromthe radiation source (1506), as depicted in FIG. 15A. In the sense mode,lines of response may be detected, but no radiation is delivered. In thefire mode depicted in FIG. 15B, the positron emission detectors nolonger occlude the patient from the radiation source and the radiationsource (1506) may apply radiation along the detected LOR. The innergantry (1502) supporting the positron emission detectors may be able torotate substantially faster than the outer gantry (1504) supporting theradiation source, which may allow for very small lag times between LORdetection and radiation response.

One example of a method that may be used with an EGRT system comprisinga gantry with separately rotatable inner and outer gantries, one or morepositron emission detectors along the gantry, one or more radiationsources mounted on the gantry, a motion system, and a microprocessor, isrepresented in FIG. 15C. The microprocessor may first determine, basedon user input and/or a pre-programmed state, whether the system is insense mode (1522). If the EGRT system is in sense mode, LOR measured bythe positron emission detectors (1530) may be collected and optionallystored in a memory of the positron emission detector and/ormicroprocessor. The microprocessor may compare the orientation anddirection of the LOR with the location of the PTV, and determine whetherthe LOR intersects the PTV (1532). If the LOR does not intersect thePTV, the microprocessor may return to the initial state (1522). If theLOR does intersect the PTV, the LOR is added to a memory queue of themicroprocessor (1534). A plurality of LOR may be stored in the memoryqueue while the EGRT system is in sense mode. In some variations, theEGRT system may initialize into sense mode at the start of a radiationtherapy session.

However, if in the initial state (1522), the microprocessor determinesthat the EGRT system is not in sense mode, or if the microprocessor mayprocess a line of response from a queue of valid lines of response(1524). Processing a LOR may comprise detecting a single coincidentpositron annihilation emission path using the positron emissiondetectors, and may optionally comprise storing data about the LOR in amemory queue of the microprocessor. The microprocessor may then comparethe location of the LOR with the location of the radiation source, e.g.,by querying the radiation source, to determine whether the radiationsource is generally aligned with the LOR (1526). If not, then themicroprocessor may not provide an instruction to the radiation source toapply radiation along the LOR, and return to the initial state (1522).If so, then the microprocessor may provide an instruction to theradiation source to fire a radiation beam along the LOR (1528). This maybe repeated until the system is returned to sense mode, or untilradiation has been delivered along all the LOR stored in the memoryqueue.

Although the foregoing invention has, for the purpose of clarity andunderstanding been described in some detail by way of illustration andexample, it will be apparent that certain changes and modifications maybe practiced, and are intended to fall within the scope of the appendedclaims.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimits of that range is also specifically disclosed. Each smaller rangebetween any stated value or intervening value in a stated range and anyother stated or intervening value in that stated range is encompassedwithin the invention. The upper and lower limits of these smaller rangesmay independently be included or excluded in the range, and each rangewhere either, neither or both limits are included in the smaller rangesis also encompassed within the invention, subject to any specificallyexcluded limit in the stated range. Where the stated range includes oneor both of the limits, ranges excluding either or both of those includedlimits are also included in the invention.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present invention, some potential andpreferred methods and materials are now described.

It must be noted that as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise. Thus, for example, reference to “ablade” includes a plurality of such blades and reference to “the energysource” includes reference to one or more sources of energy andequivalents thereof known to those skilled in the art, and so forth.

The publications discussed herein are provided solely for theirdisclosure. Nothing herein is to be construed as an admission that thepresent invention is not entitled to antedate such publication by virtueof prior invention. Further, the dates of publication provided, if any,may be different from the actual publication dates which may need to beindependently confirmed.

The preceding merely illustrates the principles of the invention. Itwill be appreciated that those skilled in the art will be able to devisevarious arrangements which, although not explicitly described or shownherein, embody the principles of the invention and are included withinits spirit and scope. Furthermore, all examples and conditional languagerecited herein are principally intended to aid the reader inunderstanding the principles of the invention and the conceptscontributed by the inventors to furthering the art, and are to beconstrued as being without limitation to such specifically recitedexamples and conditions. Moreover, all statements herein recitingprinciples, aspects, and embodiments of the invention as well asspecific examples thereof, are intended to encompass both structural andfunctional equivalents thereof. Additionally, it is intended that suchequivalents include both currently known equivalents and equivalentsdeveloped in the future, i.e., any elements developed that perform thesame function, regardless of structure. The scope of the presentinvention, therefore, is not intended to be limited to the exemplaryembodiments shown and described herein. Rather, the scope and spirit ofpresent invention is embodied by the appended claims. For all theembodiments described herein, the steps of the method need not beperformed sequentially.

1-29. (canceled) 30: A system for positioning a radiation sourcecomprising: a gantry; a radiation source mounted on the gantry; positronemission detectors mounted on the gantry, wherein the positron emissiondetectors are configured to detect a positron emission path thatintersects a planning target volume (PTV), wherein the positron emissionpath is defined by a pair of photons emitted by a positron annihilationevent; and a controller in communication with the radiation source andthe positron emission detectors, the controller configured to calculatethe time difference between the detection of each of the photons in thepair of photons, compute the location of the positron annihilation eventbased on the calculated time difference, wherein the locationcomputation has an estimation error, extend a boundary of the PTVaccording to the estimation error, determine whether the location of thepositron annihilation event is within the extended PTV, and position theradiation source with respect to the detected positron emission path ifthe location of the annihilation event is located within the extendedPTV boundary. 31: The system of claim 30, further comprising storingdata from the detected positron emission path in a memory of thecontroller. 32: The system of claim 31, wherein if the location of theevent is not located within the extended PTV boundary, storing data fromthe detected positron emission path in the memory without positioningthe radiation source with respect to the detected positron emissionpath. 33: The system of claim 30, wherein the estimation error is about5 cm. 34: The system of claim 30, wherein the radiation source isconfigured to direct radiation according to a selected probabilisticcoefficient after the radiation source is positioned with respect to thedetected positron emission path. 35: The system of claim 30, whereinextending the boundary of the PTV by the estimation error comprisesextending the boundary along an axis of extension, and wherein thecontroller is further configured to determine whether the detectedpositron emission path is substantially perpendicular to the axis ofextension. 36: The system of claim 30, wherein the controller is furtherconfigured to determine, using an image of the PTV acquired by aselected imaging modality, whether the detected positron emission pathintersects a variable density region, compute an attenuation factorbased on the density of the intersected variable density region; andwherein the radiation source is configured to direct radiation that ismodulated by the attenuation factor. 37: The system of claim 30, whereinthe detected positron emission path intersects a second PTV, and whereinthe controller is configured to extend a boundary of the second PTVaccording to the estimation error, determine, if the location of thepositron annihilation event is not within the first extended PTV,whether the location of the positron annihilation event is within thesecond extended PTV, and position the radiation source with respect tothe detected positron emission path if the location of the annihilationevent is located within the second extended PTV boundary. 38: The systemof claim 30, wherein positioning the radiation source with respect tothe detected positron emission path comprises aligning the radiationsource along the detected positron emission path. 39: The system ofclaim 30, wherein the controller is configured to position the radiationsource with respect to the detected positron emission path if thelocation of the annihilation event is located within the unextended PTVboundary. 40: A method for positioning a radiation source comprising:(a) detecting a positron emission path, wherein the positron emissionpath is defined by a pair of photons emitted by a positron annihilationevent; (b) calculating the time difference between the detection of eachof the photons in the pair of photons; (c) computing the location of thepositron annihilation event based on the calculated time difference,wherein the location computation has an estimation error; (d) extendinga boundary of a planning target volume (PTV) according to the estimationerror; (e) determining whether the detected positron emission pathintersects the PTV and whether the computed location of the positronannihilation event is within the extended boundaries of the PTV; and (f)if the computed location of the positron annihilation event is withinthe extended boundaries of the PTV, positioning a radiation source withrespect to the detected positron emission path. 41: The method of claim40, wherein positioning the radiation source comprises aligning theradiation source along the detected positron emission path. 42: Themethod of claim 40, further comprising: (g) if the detected positronemission path intersects the PTV and the computed location of thepositron annihilation event is not within the extended boundaries of thePTV, storing data of the detected positron emission path in a controllermemory without positioning the radiation source with respect to thedetected positron emission path. 43: The method of claim 40, wherein theestimation error is about 5 cm. 44: The method of claim 40, wherein step(f) further comprises using the radiation source to generate radiationaccording to a selected probabilistic coefficient. 45: The method ofclaim 40, wherein step (d) further comprises extending the boundary ofthe PTV along an axis of extension, step (e) further comprisesdetermining whether the detected positron emission path is substantiallyperpendicular to the axis of extension, and step (f) comprisespositioning the radiation source with respect to the detected positronemission path if the detected positron emission path is substantiallyperpendicular to the axis of extension, and the computed location of thepositron annihilation event is within the extended boundaries of thePTV. 46: The method of claim 40, further comprising (g) determining,using an image of the PTV acquired by a selected imaging modality,whether the detected positron emission path intersects a variabledensity region, and (h) computing an attenuation factor based on thedensity of the intersected variable density region; and step (f) furthercomprises generating radiation that is modulated by the attenuationfactor. 47: The method of claim 40, further comprising: (g) determiningwhether the detected positron emission path intersects a second PTV, (h)if the detected positron emission path intersects a second PTV,extending a boundary of the second PTV according to the estimationerror, (i) if the location of the positron annihilation event is withinthe first extended PTV or within the second extended PTV, positioningthe radiation source with respect to the detected positron emissionpath.